To this end, we showed that the agomiR-204-5p could inhibit tumor growth and metastasis in an HNSCC PDX model with repression of EMT-mediated by the SNAI2/PRC2/HDAC1 complex and inactivation of JAK2/STAT3 signaling; all of which indicates that targeting miR-204-5p is a promising and innovative therapeutic strategy. Here, STAT3 is linked to head and neck squamous cell carcinoma.